Pd-Catalyzed Cross-Coupling of Hindered, Electron-Deficient Anilines with Bulky (Hetero)aryl Halides Using Biaryl Phosphorinane Ligands

Abstract

Biaryl phosphorinane ligands derived from addition of biaryl primary phosphines to trans,trans-dibenzylideneacetone (Alison-Phos and AliPhos) form highly active ligands for Pd-catalyzed coupling of hindered, electron-deficient anilines with hindered (hetero)aryl halides, a challenging class of C−N cross-coupling reaction with few precedents. Broad substrate scope and functional group tolerance were observed under the reaction conditions. Computational studies suggest that ligands containing phenyl substituents provide greater activity through more favorable aniline binding in the catalytic cycle in comparison to alkylsubstituted phosphorinanes. A general and high-yielding procedure for the synthesis of biaryl phosphorinanes by phospha-Michael addition of primary biarylphosphines to 1,4-dien-3-ones in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), under relatively mild conditions (23−110 °C), is also described. HFIP as the solvent significantly accelerates the phospha-Michael addition, allowing the preparation of previously inaccessible ligands and higher yields overall.

HFIP in Organic Synthesis

“…In search of a suitable ligand for a challenging Pd-catalyzed cross-coupling of hindered, electron-deficient anilines with hindered (hetero)­aryl halides, Shekhar and co-workers developed a general strategy for the synthesis of biarylphosphorinanes via a phospha-Michael addition (Scheme ). Solvent screening indicated that HFIP gave the desired phospha-Michael addition product in high yield. The phosphinanones were directly converted to phosphorinanes, which were then screened for their utility as ligands.…”

Design of Benzimidazolyl Phosphines Bearing AlterableP,OorP,N-Coordination: Synthesis, Characterization, and Insights into Their Reactivity

“…The orthosubstituted, electron-poor anilines were seldom able to couple with ortho-substituted aryl chlorides, as electron-deficient anilines are poor nucleophiles. 15 Herein, we successfully demonstrated the C−N coupling of sterically hindered 2chloro-3-methylbenzonitrile with 3-fluoro-2-methylaniline using 3.0 mol % Pd loading.…”

“…The amination reactions proceeded well with the sterically demanding aryl chlorides with an aniline containing di- o -methyl groups, or even 2,6-diisopropyl substituents, with 1.0 mol % Pd loading. The ortho -substituted, electron-poor anilines were seldom able to couple with ortho -substituted aryl chlorides, as electron-deficient anilines are poor nucleophiles . Herein, we successfully demonstrated the C–N coupling of sterically hindered 2-chloro-3-methylbenzonitrile with 3-fluoro-2-methylaniline using 3.0 mol % Pd loading.…”

A Bulky and Electron-Rich N-Heterocyclic Carbene–Palladium Complex (SIPr)Ph2Pd(cin)Cl: Highly Efficient and Versatile for the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides with (Hetero)aryl Amines at Room Temperature

“…To achieve a high efficiency in this C–N cross-coupling reaction, much attention has been paid to the development of palladium catalysts with new ligands. Until now, a variety of sterically demanding and electron-rich phosphines were designed and synthesized for this purpose, and some of them, such as Buchwald’s and Hartwig’s phosphines, displayed high activities in the amination . Since the first isolation of free N -heterocyclic carbenes (NHCs) by Arduengo, Pd­(II)-NHC precatalysts exhibit much promise in palladium-catalyzed amination thanks to their strong electron donation and the steric protection of the palladium center .…”